This application is a 371 of PCT/AU96/00638 filed Oct. 10, 1996.
The present invention relates to potent, xcex21-specific beta adrenoreceptor blockers w a short duration of action and to a method for the treatment and/or prophylaxis of conditions for which potent, xcex21-specific beta adrenoreceptor blockers with a short duration of action in the systemic circulation would be particularly advantageous.
The class of drugs known as xcex2-blockers are well known in the art for treatment of cardiac disorders and particular ophthalmological conditions. However, the optimum combination of properties of such agents depends critically on the condition being treated. Thus, in the long-term treatment of cardiovascular diseases such as hypertension and cardiac arrhythmias, the combination of xcex21-selectivity with high potency, good oral bioavailability and long plasma half-life and duration of action are usually considered optimal, since xcex21-selective compounds have a low incidence of side-effects associated with blockade of xcex22-receptors, such as asthma, and the remaining properties permit treatment by oral administration usually on a once a day basis.
In other conditions where xcex21-selectivity is preferred, some of these properties are not optimal. In ocular administration for the treatment of glaucoma oral availability and long plasma half-life may lead to unwanted systemic side-effects. In the management of cardiac arrhythmias which may arise during induction of anaesthesia or in the care of critically ill patients, short systemic half-life permits rapid control of arrhythmias without the risk of inducing long acting beta blockade. Treatment of glaucoma requires a drug which is well absorbed into the eye. However rapid clearance from the systemic circulation by metabolism to inactive metabolites, after passing through the eye or being swallowed via the naso-lachrymal duct, ensures that treatment is limited to the eye and side-effects are minimised For short-term systemic administration a combination of xcex21-selectivity and short half-life is ideal. For both conditions high potency is required as there is a limit to the practical concentrations which may be formulated into eyedrops, and high potency reduces the dose needed for systemic administration, which tends to be greater for compounds with short half-lives than conventional beta blockers.
Accordingly there is a need to develop xcex21-specific blockers with high potency and a short duration of action in the systemic circulation.
Short acting beta blockers have been described in U.S. Pat. No. 4,966,914, U.S. Pat. No. 4,455,317, U.S. Pat. No. 4,810,717, U.S. Pat. No. 4,593,119, U.S. Pat. No. 5,013,734 and European Patent 041491. All of the short acting beta blocking drugs described in these patents incorporate an easily hydrolysed ester function in their structures.
However, it is difficult to say that the compounds of the above inventions are entirely adequate with regard to the optimum combination of properties required. These may be summarised as (1) adequate blocking effect on the receptor (2) specificity for the xcex21 receptor and (3) a short duration of action in the systemic circulation.
Accordingly there is a need to develop xcex2-blocking drugs which satisfactorily combine the aforementioned properties (1) to (3).
U.S. Pat. No. 4,816,604 describes the group of compounds of formula (I) as xcex21-selective beta blockers. 
wherein
R is phenyl or phenyl monosubstituted or independently disubstituted or independently trisubstituted by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 35,
R1 is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alklythio of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, halogen of atomic number of from 9 to 35, trifluoromethyl, 1-pyrrolyl, cyano, carbamoyl, alkenyl of 2 to 5 carbon atoms, alkenyloxy of 3 to 5 carbon atoms wherein the double bond is not attached to the carbon atom adjacent to the oxygen atom, or alkanoyl of 1 to 5 carbon atoms,
R2 is alkyl of 1 to 4 carbon atoms, cycloalkyl of 5 to 7 carbon atoms, cycloalkylalkyl of 3 to 7 carbon atoms in the cycloalkyl moiety and of 1 to 4 carbon atoms in the alkyl moiety, phenyl, phenylalkyl of 7 to 10 carbon atoms, or phenyl or phenylalkyl of 7 to 10 carbon atoms monosubstituted or independently disubstituted or independently trisubstituted in the phenyl ring by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 35.
A is alkylene of 2 to 5 carbon atoms.
X is a bond, an oxygen or a sulfur atom
Y is an oxygen or a sulfur atom, and either Z is an oxygen atom and n is 2 or 3 or Z is a bond and n is 1, 2 or 3, with the provisos, that
(a) when R2 is alkyl, then Z is an oxygen atom and the group xe2x80x94NHxe2x80x94Axe2x80x94Xxe2x80x94R is other than the moiety of formula
xe2x80x94NHCH(CH3)CH2CH2Ph
xe2x80x94NHCH(CH3)CH2CH2OPh
xe2x80x94NHCH(CH3)CH2CH2CH2OPh
or
xe2x80x94NHCH(CH3)CH2CH(CH3)OPh
(b) when R2is alkyl and X is a bond or an oxygen atom, then Y is an oxygen atom, and
(c) when
R2 is unsubstituted or monosubstituted phenyl,
X is a bond and
Z is an oxygen atom, or
when R2 is cycloalkyl or cycloalkylalkyl and
X is a bond,
then R1 is other than hydrogen, and physiologically acceptable hydrolysable derivatives thereof having the hydroxy group in the 2 position of the 3-aminopropoxy side chain in esterified form, or a pharmaceutically acceptable acid addition salt form thereof.
We have now surprisingly found that a small group of compounds selected from the class generally described in U.S. Pat. No. 4,816,604 have the desirable combination of the aforementioned characteristics (1) to (3). They are particularly active, xcex21-specific and exhibit a short duration of action in the systemic circulation. Such a short duration of action in the systemic circulation is unexpected and could not be predicted as the compounds of the invention are not dependant upon the easily hydrolysed ester groups associated with prior art xcex2-blockers with a short plasma half-life.
Accordingly the present invention provides compounds of formula (Ia) as potent, xcex21-specific beta blockers with a short duration of action in the systemic circulation, 
wherein
R is 3xe2x80x2,4xe2x80x2-dimethoxyphenyl, R1 is hydrogen, and R2 is selected from methyl, ethyl, propyl, isobutyl and isopropyl; or
R is 3xe2x80x2,4xe2x80x2-dimethoxyphenyl, R1 is selected from fluorine, chlorine and bromine, and R2 is selected from methyl, ethyl, propyl, isopropyl, isobutyl and cyclopropylmethyl; or
R is 4xe2x80x2-methoxyphenoxy, R1 is selected from hydrogen, fluorine, chlorine and bromine, and R2 is selected from methyl, ethyl, propyl, isopropyl, isobutyl and cyclopropylmethyl; or
R is 3xe2x80x2,4xe2x80x2-dimethoxyphenyl, R1 is cyano, and R2 is cyclopropylmethyl or isobutyl; or
R is 4xe2x80x2-methoxyphenoxy, R1 is cyano, and R2 is isobutyl; and physiologically acceptable hydrolysable derivatives thereof having the hydroxy group in the 2-position of the 3-aminopropoxy side chain in esterified form,
in their racemic and optically active forms, and their pharmaceutically acceptable acid addition salts.
In accordance with a preferred aspect, the present invention provides compounds of formula (Ia) as stated above,
wherein
R is 3xe2x80x2,4xe2x80x2-dimethoxyphenyl, R1 is hydrogen, and R2 is selected from methyl, ethyl, propyl, isobutyl and isopropyl; or
R is 4xe2x80x2-methoxyphenoxy, R1 is hydrogen and R2 is selected from methyl, ethyl, propyl, isopropyl, isobutyl and cyclopropylmethyl; or
R is 3xe2x80x2,4xe2x80x2-dimethoxyphenyl, R1 is cyano, and R2 is cyclopropylmethyl; or
R is 4xe2x80x2-methoxyphenoxy, R1 is cyano, and R2 is isobutyl;
R is 3xe2x80x2,4xe2x80x2-dimethoxyphenyl, R1 is bromine, and R2 is methyl;
and physiologically acceptable hydrolysable derivatives thereof having the hydroxy group in the 2-position of the 3-aminopropoxy side chain in esterified form,
in their racemic and optically active forms, and their pharmaceutically acceptable acid addition salts.
In a further aspect of the present invention is provided a method for the treatment and/or prophylaxis of conditions for which potent, xcex21-specific beta blockers with a short duration of action in the systemic circulation would be particularly advantageous which comprises administering to a patient in need of such treatment and/or prophylaxis an effective amount of a compound of formula (Ia).
The present invention also provides the use of a compound of formula (Ia) in the manufacture of a medicament for the treatment and/or prophylaxis of conditions for which potent, xcex21-specific beta blockers with a short duration of action in the systemic circulation would be particularly advantageous.
Preferred compounds, in accordance with the invention are:
1-(4-(2-methoxyethoxy)phenoxy)2-hydroxy-3-(2-(4-methoxyphenoxy)ethylamino)propane;
1-(2-cyano-4-(2-(2-methylpropoxy)ethoxy)phenoxy)2-hydroxy-3-(2-(4-methoxyphenoxy)ethylamino)propane;
S(xe2x88x92)1-(4-(2-ethoxyethoxy)phenoxy)2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethylamino)propane;
1-(2-cyano-4-(2-cyclopropylmethoxyethoxy)phenoxy)-2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethylamino)propane; and
1-(4-(2-ethoxyethoxy)phenoxy)-2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethylamino) propane;
Particularly preferred compounds are
1-(4-(2-ethoxyethoxy)phenoxy)-2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethylamino) propane and
S(xe2x88x92)1-(4-(2-ethoxyethoxy)phenoxy)2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethylamino)propane.
Preferred indications for which potent, xcex21-specific beta blockers with a short duration of action in the systemic circulation would be particularly advantageous are ocular treatment of glaucoma, parenteral treatment of cardiac arrhythmias and acute myocardial infarction and parenteral treatment of other cardiac disorders where prolonged blockade of xcex21-adrenoreceptors is undesirable.
Physiologically acceptable hydrolysable derivatives are those derivatives which act as prodrugs and under physiological conditions are cleaved to the corresponding compounds having a hydroxy group in the 2 position of the 3-aminopropoxy side chain.
A group of prodrug derivatives which are esterified forms of the compounds of formula (Ia) are e.g. the compounds of formula (E) 
wherein R, R1 and R2 are as defined above and Re is alkyl of 1 to 12 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl, phenylalkyl of 7 to 12 carbon atoms, or phenyl or phenylalkyl of 7 to 12 carbon atoms monosubstituted in the phenyl ring by alkyl of 1 to 4 carbon atoms, or mono- or independently di- or independently trisubstituted in the phenyl ring by halogen of atomic number from 9 to 35, or mono- or independently di- or independently trisubstituted in the phenyl ring by alkoxy of 1 to 4 carbon atoms.
Preferred are the compounds wherein the hydroxy group in the 2 position of the 3-aminopropoxy side chain is in unesterified form.
A compound of the invention may be obtained by a process described in U.S. Pat. No. 4,816,604, comprising reacting a corresponding compound of formula (II), 
wherein R1 and R2 are as defined above and Rx is a group capable of reacting with a primary amine to give a 2-amino-1-hydroxyethyl group, with an appropriate compound of formula (III),
H2NCH2CH2xe2x80x94Rxe2x80x83xe2x80x83(III)
wherein R is as defined above, and, where required, appropriately esterifying the 2 position of the 3-aminopropoxy side chain in the resulting compound of formula (Ia).
The amination process may be effected in a conventional manner for the production of analogous 3-amino-2-hydroxypropoxyaryl compounds. For example, Rx may be a group of formula 
or a derivative of this group, e.g. a group of formula xe2x80x94CH(OH)xe2x80x94CH2L, wherein L is chlorine, bromine or a group Ry-SO2xe2x80x94Oxe2x80x94, wherein Ry is phenyl, tolyl or lower alkyl. L is especially chlorine. The reaction is preferably effected in ethanol or in an appropriate ether such as dioxane. Optionally an excess of the amine may be used as solvent. Alternatively, the reaction may be effected in a fusion melt. Suitable reaction temperatures may be from about 20xc2x0 to about 200xc2x0 C., conveniently the reflux temperature of the reaction mixture when a solvent is present.
The optional esterification of the 2 hydroxy group in the side chain may be effected in a manner known for the production of analogous esters of 3-amino-2-hydroxypropoxyaryl compounds, if necessary using selective reactions when other reactive groups are present.
Free base forms of the compounds of the invention may be converted into pharmaceutically acceptable acid addition salt forms in a conventional manner and vice versa. Suitable acids for acid addition salt formation include, for example, hydrochloric, hydrobromic, malonic and fumaric acids.
In the compounds of the invention, the carbon atom in the 2 position of the 3-aminopropoxy side chain is asymmetrically substituted. The compounds may thus exist as mixtures of the two optical forms, such as in the racemic form, or in individual optical isomer form. The preferred optical isomer has the S configuration at this asymmetrically substituted carbon atom of the 3-aminopropoxy side chain. Individual optical isomer forms may be obtained in a conventional manner, for example by using optically active starting materials or by fractional crystallisation of racemate salts using optically active acids.
A compound used as a starting material may be obtained in a conventional manner.
In particular, a compound of formula (II) may be obtained by introducing via O-alkylation a group xe2x80x94OCH2xe2x80x94Rx into a compound of formula (IV), 
wherein R1 and R2 are as defined above. The compound of formula (IV) preferably is reacted in anionic form.
A compound of formula (IV) where R1 is hydrogen may be obtained by selectively etherifying 1,4-dihydroxybenzene at one of the hydroxy groups, e.g. by reaction with a molar equivalent of a compound of formula Lxe2x80x94CH2CH2Oxe2x80x94R2 wherein R2 and L are as defined above, preferably in an inert solvent such as acetone and in the presence of a base such as potassium carbonate. Alternatively a compound of formula (IV) where R1 is hydrogen may be obtained by deprotecting a corresponding compound of formula V, 
wherein
R2 are as defined above and
Bz is a protecting group, e.g. benzyl or tetrahydropyranyl, under appropriate conditions, e.g. with palladium on charcoal or by acidic hydrolysis.
A compound of formula (V) may e.g. be obtained by appropriately etherifying 4-benzyloxyphenol, e.g. with a derivative Lxe2x80x94CH2CH2Oxe2x80x94R2, wherein L and R2 are as defined above. L is preferably 4xe2x80x2-toluenesulfonate.
A compound of formula (IV) where R1 is bromine may be obtained by monobromination of the corresponding compound of formula (IV) where R1 is hydrogen. The resulting bromo compound may be converted into a compound of formula (IV) where R1 is cyano by, for example, treatment with cuprous cyanide in dimethyl formamide.
Insofar as the preparation of any particular starting material is not particularly described, this may be effected in conventional manner.